Abstract

Background

Combining chemotherapy with immune checkpoint inhibitors may have additive or synergistic clinical activity. The objective of this phase I study was to assess safety and dose limiting toxicities (DLTs) of combining mFOLFOX6 and pembrolizumab in advanced gastrointestinal (GI) malignancies.

Methods

This phase I trial used a 3 + 3 dose escalation design and included patients with advanced GI malignancies for which FOLFOX is indicated. Study treatment consisted of a phased regimen with patients receiving two cycles of mFOLFOX6 every 2 weeks followed by subsequent treatments with mFOLFOX6 plus pembrolizumab (75mg or 200mg) IV every 2 weeks. A DLT was considered if there was at least a possible causal relationship to pembrolizumab or the combination and occurred in weeks 4-6 of treatment (Cycles 3 and 4). Safety measures, disease response and biomarkers were assessed.

Results

Ten patients (6 male) with a median age of 60 years (26-72 years) with advanced colon (7), biliary (1), small intestine (1) and gastric (1) malignancies were enrolled to complete this phase I study cohort. Nine had received prior FOLFOX treatment. Three patients enrolled on the 75 mg dose of pembrolizumab and no DLTs were observed. The next seven patients were dose escalated to 200 mg of pembrolizumab. Of the seven patients treated in the 200 mg cohort, one patient was not evaluable for DLTs due to dose reductions to FOLFOX in the first two cycles. There were no DLTs observed at this dose level. The most common grade 3 or 4 adverse events were neutropenia (40%) and hyponatremia (30%). In the 75mg cohort, one patient was evaluable for disease response and had progressive disease. As of April 19, 2016, the following best overall responses have been observed: 2 (28.6%) partial response, 4 (57.1%) stable disease, and 1 (14.3%) progressive disease. Biomarker assessments will be presented.

Conclusions

The combination of mFOLFOX6 with pembrolizumab (200 mg IV every 2 weeks) has an acceptable safety profile. Further assessment of safety and efficacy is being evaluated in phase II dose-expansion cohorts.